신장내과 강혜란 Thyroid function in chronic kidney disease

Thyroid hormone metabolism  The kidney normally contributes to the clearance of iodide, by glomerular filtration  In advanced renal failure  iodide excretion ↓ → plasma inorganic iodide concentration ↑  intrathyroidal iodide pool ↑ → uptake of radiolabeled iodide ↓  total body inorganic iodide ↑ → potentiallly block thyroid hormone production (the Wolff-Chaikoff effect) => slightly higher frequency of goiter and hypothyroidism in patients with CKD

Thyroid hormone metabolism : Low T3 levels  Most patients with ESRD : plasma levels of free triiodothyronine (T3) ↓  T4 (thyroxine) → T3 ↓ in the periphery  not associated with T4 → rT3 ↑ (metabolically inactive reverse T3), plasma rT3 levels are typically normal  Chronic illness vs uremic patient  T4 (thyroxine) → T3 ↓, T4 → rT3 ↑ → total T3 concentration ↓ → circulating levels of serum T3 sulfate ↑ d/t renal clearance ↓ (ESRD)

Thyroid hormone metabolism : Low T3 levels  Low levels of total T3 : reflect metabolic acidosis, reduced protein binding  Circulating thyroid hormones : bound to thyroid hormone-binding globulin (TBG)  Circulating TBG, albumin levels : typically normal in uremia  urea, creatinine, indoles, phenols (in renal failure)  strongly inhibit protein binding of T4  may inhibit T4 binding to solid-phase matrices (resin, activated charcoal) in measuring T4 levels → serum T4 levels ↓  Free fatty acids, heparin : interfere with T4 binding to TBG  routine use of heparin : transient elevation in serum T4 levels that commonly occurs during hemodialysis

Thyroid hormone metabolism : Low T3 levels  Low plasma free T3 levels may also be associated with  decreased overall survival  presence of the malnutrition-inflammation syndrome (cytokine ↑)

Thyroid hormone metabolism : Hypothalamic-pituitary dysfunction  The plasma concentration of TSH : usually normal in CKD  TSH response to exogenous TRH is often blunted and delayed  Reduced renal clearance (TSH, TRH : normally cleared by the kidney)  Disordered function at the hypothalamic-pituitary level (induced by uremic toxins)

Clinical significance  Low T3  associated with all-cause and cardiovascular mortality in uremic patients  in one study of 210 hemodialysis patients, low T3 concentrations  persistent throughout the 38-month study  associated with a higher risk of all-cause and cardiovascular mortality  hazard ratios :  Low T4, but not thyroid-stimulating hormone (TSH)  associated with all-cause and cardiovascular mortality  T3, T4, or TSH did not correlate with noncardiovascular mortality

Clinical significance  Substantial clinical overlap between CKD and hypothyroidism  total and plasma free T3 levels ↓  Symptoms ; cold intolerance, puffy appearance, dry skin, lethargy, fatigability, and constipation  the frequency of goiter is markedly increased in end-stage renal disease  Hypothyroidism  occur in patients with renal disease, with a frequency that may be slightly greater than that in the general population  Diagnosis : serum TSH ↑, serum-free T4 ↓, TBG normal  Delayed deep tendon relaxation may be a confirmatory clinical finding

Clinical significance

 Thyroid gland size ↑  often increased in patients with CKD  How this occurs is not clear (accumulation of an unidentified goitrogen ? )  Nodules and carcinoma ↑  slightly higher frequency in patients with CKD  Why this might occur is not known

Am J Kidney Dis (6):

Introduction  Abnormal thyroid function in dialysis patients has been reported  related to uremic toxins, protein malnutrition, and inflammation  subclinical thyroid dysfunction -> associated with increased mortality  Subclinical thyroid dysfunction  common endocrine condition in the general population  altered thyrotropin (TSH) levels, normal thyroid hormone levels  Subclinical hyperthyroidism  associated with atrial fibrillation, cardiovascular (CV), all-cause mortality in the general population  Subclinical hypothyroidism  more frequent in areas with sufficient iodine intake  association with heart failure, mortality

Introduction  Euthyroid sick syndrome  “nonthyroidal illness” syndrome, “low T3 [triiodothyronine] syndrome,”  low levels of circulating T3  normal or slightly decreased TSH and tetraiodothyronine (thyroxine [T4])  adaptation to protein and energy wasting in critical illness >> genuine thyroid disease  associated with poor prognosis in severely ill patients with sepsis, CHF, LC

Introduction  Subclinical hypothyroidism : ≥ 25% of patients with CKD  Subclinical hyperthyroidism : not to be increased (compared general population)  Euthyroid sick syndrome : ≥ 70% of patients with ESRD  be associated with particularly poor prognosis in this cohort  The impact of subclinical thyroid disorders on specific CV events and mortality is largely unknown in dialysis patients  Previous experimental research showed  close link of thyroid dysfunction with impaired artery vasodilation, cardiac contractility  low T3 levels : related to cardiomyopathy, arterial stiffness, and carotid therosclerosis in dialysis patients  Aim  to analyze whether subclinical thyroid disorders were associated with CV events and mortality in dialysis patients

 Study Design  Prospective multicenter cohort study  Setting & Participants  explored in 1,000 diabetic hemodialysis patients from 178 centers in Germany  Predictor : Thyroid status  euthyroidism  subclinical hyperthyroidism  subclinical hypothyroidism  euthyroid sick syndrome  Outcomes  During 4 years’ follow-up  End points : sudden cardiac death, myocardial infarction, stroke, combined CV events, and overall mortality  Measurements  TSH, free T3, and free T4 levels at baseline

Result  Euthyroid Sick synd. (HR : 2.03; 95% CI, )  Subclinical Hyperthyroidism (HR : 2.74; 95% CI, )  Euthyroid sick synd. (HR : 2.97; 95% CI, )

 Conclusions  Sudden cardiac death  influenced by subclinical hyperthyroidism, euthyroid sick syndrome  All cause mortality  associated strongly with euthyroid sick syndrome  Regular assessment of thyroid status may help estimate the cardiac risk of dialysis patients